KU124 (9,10,10-trioxo-N-(2-phenylphenyl)thioxanthene-3-carboxamide) as a novel inhibitor of TASK-1

KU124 (9,10,10-trioxo-N-(2-phenylphenyl)thioxanthene-3-carboxamide) as a novel inhibitor of TASK-1

TASK-1 is a two-pore K+ leak channel. The name, TASK-1, stands for TWIK-related acid-sensitive potassium channel 1, and this channel is encoded by the KCNK3 gene. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular s...

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Main Authors: Ana Dumani, Annette Jacob, Diego Chavez, Abena Amankwaa, Ramish Zahed, Martha Julemis, Hinaben Patel, Joana Lopez, Steven Almazan, Patrick Martins, Anthony Contreras, Sofiia Korotka, Gianna Kiszka, Alexander Aleynik, Justin Patino, David Graham, Megan Blaisdell, Youssef Elhowary, Shuayb Yousuf, Chelsea Pelley, Jenna Marciano, Jessica Best, Rhustie Valdizno, Nikki Mastrodomenico, Jonelle Brown, Sarah Schwartz, Irene Anin, Yara Farrag, Rinchu George, Gianna Medeiros, Sophia Lang, Marilyn Dennis, Oluwatoni Awoleye, Lamont Lee, Ericka Salgado, Diana Figueroa Chea, Thomas Walter Comollo
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-06-01
Series:Frontiers in Pharmacology
Subjects:
TWIK-related acid-sensitive potassium channel 1
virtual screening
inhibitor
KU124
molecular dynamics
thallium flux
Online Access:https://www.frontiersin.org/articles/10.3389/fphar.2025.1577171/full
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Summary:TASK-1 is a two-pore K+ leak channel. The name, TASK-1, stands for TWIK-related acid-sensitive potassium channel 1, and this channel is encoded by the KCNK3 gene. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular smooth muscle cells. TASK-1 inhibition is a mechanism of action for some respiratory stimulants, such as doxapram. TASK-1 channels have also been suggested to play a role in circumventing cell apoptosis in a population of non-small-cell lung cancer cells. We propose that the inner vestibule of the TASK-1 channel, a known binding site of known TASK-1 inhibitors, BAY10000493 and BAY2341237, can be exploited via virtual screening to find other novel TASK-1 inhibitors. Our results show that by targeting the inner vestibule site, we found an active TASK-1 inhibitor. We suspect that this region of interest can be further exploited to discover additional TASK-1 inhibitors. Our initial success lends validity to our virtual screening methodology and parameters. In this study, we identified a novel TASK-1 inhibitor, KU124, which we verified using an in vitro assay.
ISSN:1663-9812

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